This systematic review provides a high-quality, comprehensive summary of recommendations on hypertension (HT) and type 2 diabetes mellitus (T2DM), accentuating patient blood pressure, HbA1c levels, patterns of drug treatment, management, and screening of these diseases. The overall objective of the review is to support adapting existing clinical practice guidelines in Indonesia, Vietnam, and Myanmar. The database PubMed and the web search engines Google and Google Scholar were searched from October to December 2019 for evidence-based guidelines covering the overall disease management in Europe, the United States of America, and low and middle-income countries (Indonesia, Vietnam, and Myanmar-IVM later on). Nine studies were selected for the review, seven concerning HT and five T2DM. Guidelines in IVM and Europe identified HT as increased blood pressure (BP; ≥140/90 mmHg). IVM guidelines also recommended commencing drug treatment if lifestyle interventions were not successful. Four international HT guidelines recommended monitoring BP every few months, and the other three guidelines gave recommendations based on the patient's current BP levels. All five T2DM guidelines recommended target HbA1c levels below 7%-6.5%, but only IVM guidelines included re-examination every 3-6 months. Metformin was recommended as the first choice of medical treatment, if not contraindicated. Amid the guidelines' recommendations, there were no major variations in the Class of recommendation and Level of evidence (except IVM guidelines where COR and LOE were missing). Revision and completion of IVM guidelines by this grading system would enhance evidence-based and informed decisions in clinical care.

Despite key advances in the treatment of prostate cancer (PCa), a proportion of men have de novo resistance, and all will develop resistance to current therapeutics over time. Aberrant lipid metabolism has long been associated with prostate carcinogenesis and progression, but more recently there has been an explosion of preclinical and clinical data which is informing new clinical trials. This review explores the epidemiological links between obesity and metabolic syndrome and PCa, the evidence for altered circulating lipids in PCa and their potential role as biomarkers, as well as novel therapeutic strategies for targeting lipids in men with PCa, including therapies widely used in cardiovascular disease such as statins, metformin and lifestyle modification, as well as novel targeted agents such as sphingosine kinase inhibitors, DES1 inhibitors and agents targeting FASN and beta oxidation.

Exposure of pregnant F0 mouse dams to the obesogen tributyltin (TBT) predisposes unexposed male descendants to obesity and diverts mesenchymal stem cells (MSCs) toward the adipocytic lineage. TBT promotes adipogenic commitment and differentiation of MSCs, in vitro. To identify TBT-induced factors predisposing MSCs toward the adipocytic fate, we exposed mouse MSCs to TBT, the PPARγ-selective agonist rosiglitazone or the RXR-selective agonist LG-100268. Then we determined their transcriptomal profiles to determine candidate microRNAs (miR) regulating adipogenic commitment and differentiation. Of the top 10 candidate microRNAs predicted by Ingenuity Pathway Analysis, miR-21, miR-33 and miR-223 were expressed consistent with an ability to differentially regulate target genes during adipogenesis. 24-hour exposure to 50 nM TBT caused miR-223 levels in MSCs to increase; expression of its target genes ZEB1, NFIB, and FOXP1 was decreased. ROSI and TBT increased miR-223 levels. This induction was inhibited by the PPARγ antagonist T0070907 but not by the RXR antagonists HX531 or UVI3003, placing miR-223 downstream of PPARγ. Chromatin immunoprecipitation confirmed TBT-induced binding of PPARγ to regulatory elements in the miR-223 promoter. miR-223 levels were elevated in white adipose tissue of F2 and F3 male descendants of pregnant F0 mouse dams exposed to 50 nM TBT throughout gestation. miR-223 levels were potentiated in males fed with an increased fat diet. We infer that TBT induced miR-223 expression and increased adipogenesis in MSCs through the PPARγ pathway and that transgenerationally increased expression of miR-223 plays an important role in the development of obesity caused by TBT exposure.

Over the years, there have been opinions on whether to reduced blood pressure (BP) to a different levels in patients with diabetes mellitus. Hence, this study investigated the efficacy of the co-administration of losartan (angiotensin receptor blocking antihypertensive agent) with metformin and/or glibenclamide (antidiabetic agents) on hypertensive-diabetic experimental rats induced by NG-nitro-l-arginine-methyl-ester hydrochloride (l-NAME), and streptozotocin (STZ). STZ (45 mg/kg, i.p.)-induced diabetic rats combined with l-NAME (40 mg/kg, p.o.)-induced hypertension were allotted into different groups. Group 1 received distilled water (10 mL/kg) and served as normal control, group 2 comprised hypertensive diabetic rats with distilled water, groups 3-5 were hypertensive-diabetic rats but received combination treatments of losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide daily for 8 weeks, respectively. Our finding revealed no changes in the body weights, but there was a significant increase in fasting blood sugar levels in l-NAME - STZ-induced hypertensive-diabetes, which were lowered by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide treatments. Moreover, the increased systolic-BP, mean arterial pressure but not diastolic-BP and heart rate by l-NAME + STZ were attenuated more significantly by losartan + metformin + glibenclamide between weeks 2-8 relative to hypertensive-diabetic control. l-NAME + STZ-induced elevated levels of lactate dehydrogenase and creatinine kinase, were differentially reversed by losartan + metformin, losartan + glibenclamide, and losartan + metformin + glibenclamide. However, l-NAME + STZ-induced decreased nitrite level was significantly restored by all treatments, suggesting increased nitrergic transmission. Additionally, l-NAME + STZ-induced degeneration of pancreatic islet and myocardial cells were dramatically alleviated by losartan + metformin + glibenclamide treatments. Our findings suggest hyperglycemia with raised systolic-BP should be managed with losartan combined with both metformin and glibenclamide than single combination of losartan with antidiabetics.

Metformin is the biguanide of hepatic insulin sensitizer for patients with non-alcohol fatty liver disease (NAFLD). Findings regarding its efficacy in restoring blood lipids and liver histology have been contradictory. In this study, we explore metformin's preventive effects on NAFLD in leptin-insensitive individuals. We used liver tissue, serum exosomes and isolated hepatocytes from high-fat diet (HFD)-induced Zucker diabetic fatty (ZDF) rats and leptin receptor (Lepr) knockout rats to investigate the correlation between hepatic Lepr defective and liver damage caused by metformin. Through immunostaining, RT-PCR and glucose uptake monitoring, we showed that metformin treatment activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) and its downstream cytochrome C oxidase (CCO). This leads to overactivation of glucose catabolism-related genes, excessive energy repertoire consumption, and subsequent hepatocyte pyroptosis. Single-cell RNA sequencing further confirmed the hyper-activation of glucose catabolism after metformin treatment. Altogether, we showed that functional Lepr is necessary for metformin treatment to be effective, and that long-term metformin treatment might promote NAFLD progression in leptin-insensitive individuals. This provides important insight into the clinical application of metformin.

Polycystic ovary syndrome (PCOS) is a common reproductive and metabolic disorder that is closely correlated with insulin resistance. Sex hormone-binding globulin (SHBG) is an important carrier for regulating androgen activity and is affected by insulin level, which is related to metabolic abnormalities and long-term prognosis of PCOS. Insulin sensitizer pioglitazone can improve the SHBG level and dyslipidaemia in PCOS, but the mechanism remains unclear. We investigated liver SHBG expression, liver lipid levels, and the effects and potential mechanisms of pioglitazone on reproductive and metabolic disorders in a rat model of polycystic ovary syndrome with insulin resistance (PCOS-IR). PCOS-IR was induced by letrozole and a high-fat diet. Metformin was used as a positive control. Additionally, dihydrotestosterone and oleic acid combined with palmitic acid were used to induce the HepG2 cell models with IR. The cells were exposed to pioglitazone alone or in combination with a hepatocyte nuclear factor (HNF)-4α inhibitor. Changes in biochemical characteristics were analysed using an enzyme-linked immunosorbent assay. Vaginal smears were used to analyse the oestrous cycle, and ovarian histology was used to analyse the changes in ovarian morphology. The degree of IR in vivo and in vitro was measured using the hyperinsulinaemic-euglycaemic clamp and glucose oxidase techniques. The levels of key anabolism-related proteins, including SHBG, HNF-4α, and peroxidase proliferator-activated receptor (PPAR-γ), were measured using western blots. Pioglitazone and metformin significantly increased the SHBG levels in the sera and livers. Compared to metformin, pioglitazone significantly improved the lipid droplet deposition, triglyceride (TG) and total cholesterol (TC) levels, HNF-4α protein expression, and weights of the livers in the PCOS-IR rats. After applying pioglitazone with an HNF-4α inhibitor in the PCOS-IR cell models, we found that pioglitazone may increase SHBG and improve IR, TG, and TC levels by upregulating HNF-4α. Similar to metformin, pioglitazone also restored the oestrous cycle and ovarian morphology, ameliorated IR and hyperandrogenaemia in the PCOS-IR rats. Our findings hint at the value of HNF-4α in the treatment of PCOS by PIO, which could shed light on potential targets that may be used in treatments for PCOS with metabolic disorders.

Following the publication of this paper, it was drawn to the Editor's attention by concerned readers that several of the cellular images shown in Figs. 6A and 8A, the scratch‑wound assay images shown in Fig. 5A, the western blotting data in Figs. 2C and 7A and the Matrigel invasion assays in Fig. 5C were strikingly similar to data appearing in different form in other articles by different authors. Owing to the fact that the contentious data in the above article had already been published elsewhere, or were already under consideration for publication, prior to its submission to International Journal of Molecular Medicine, the Editor has decided that this paper should be retracted from the Journal. The authors were asked for an explanation to account for these concerns, but the Editorial Office did not receive a reply. The Editor apologizes to the readership for any inconvenience caused. [International Journal of Molecular Medicine 36: 204‑214, 2015; DOI: 10.3892/ijmm.2015.2217].

It is estimated that more and more couples suffer from fertility and pregnancy maintenance disorders. It is associated with impaired androgen secretion, which is influenced by many factors, ranging from genetic to environmental. It is also important to remember that fertility disorders can also result from abnormal anatomy of the reproductive male and female organ (congenital uterine anomalies - septate, unicornuate, bicornuate uterus; acquired defects of the uterus structure - fibroids, polyps, hypertrophy), disturbed hormonal cycle and obstruction of the fallopian tubes resulting from the presence of adhesions due to inflammation, endometriosis, and surgery, abnormal rhythm of menstrual bleeding, the abnormal concentration of hormones. There are many relationships between the endocrine organs, leading to a chain reaction when one of them fails to function properly. Conditions in which the immune system is involved, including infections and autoimmune diseases, also affect fertility. The form of treatment depends on infertility duration and the patient's age. It includes ovulation stimulation with clomiphene citrate or gonadotropins, metformin use, and weight loss interventions. Since so many different factors affect fertility, it is important to correctly diagnose what is causing the problem and to modify the treatment regimen if necessary. This review describes disturbances in the hormone secretion of individual endocrine organs in the context of fertility and the maintenance of pregnancy.

Obesity is a global pandemic and is cause of serious concern in all regions of the world. It is important to raise the attention of health care professionals in order to provide early treatment of patients with obesity. Obesity management, however, varies greatly amongst endocrinologists with respect to attitudes to diagnosis and treatment. Aim of this study was to identify practices and needs of Italian endocrinologists with respect to people with obesity.

Age-related macular degeneration (AMD) is the leading cause of severe loss of central vision among people over 50. The pathophysiology of the disease is multifactorial and can be attributed to genetics, aging, inflammation, environmental factors, and lifestyle factors including smoking, diet, obesity, and alcohol consumption. While there is no treatment for dry AMD, the current standard treatment for wet AMD is an intraocular injection of anti-vascular endothelial growth factor-an effective, yet expensive, therapy that requires ongoing treatment. As the aging population continues to grow, and AMD diagnoses continue to rise, new treatments should be explored to reduce vision complications and decrease treatment burdens. Many systemic conditions have progressive pathological changes that may affect AMD, particularly those affecting systemic vasculature like diabetes and cardiovascular status. Consequently, systemic drugs used to treat coexistent systemic diseases may influence some of the pathogenic mechanisms of AMD and lead its progression or delay. In this review we explore the current literature to summarize the findings of the reported effects of antihypertensives, immunosuppressants, cholesterol lowering agents, non-steroidal anti-inflammatory drugs, dopamine precursors, hypoglycemic agents, and anticoagulants on AMD.

Euglycemic diabetic ketoacidosis (EDKA) is an uncommon diabetic complication with increasing prevalence and is associated with the use of sodium-glucose co-transporter 2 inhibitors (SGLT2i). We report the case of a 77-year-old female patient with type 2 diabetes mellitus, treated with metformin/linagliptin and empagliflozin, who initiated a slurred speech and altered level of consciousness in the postoperative period of a cholecystectomy. On observation, the patient presented with Kussmaul breathing and mucosal dryness and was ketotic. Laboratory exams showed metabolic acidosis with an elevated anion gap, normoglycemia, and positive ketonemia. Fluid replacement with dextrose solution and continuous insulin infusion were initiated, with progressive clinical and laboratory improvement. On discharge, she showed resolution of symptoms, and empagliflozin was discontinued from her usual medication. Despite the warnings of European and American medical agencies in 2015/2016, EDKA remains a challenging diagnosis due to its unspecific and insidious symptoms.

Head and neck cancers represent a significant portion of cancer diagnoses, with head and neck cancer incidence increasing in some parts of the world. Typical treatment of early-stage head and neck cancers includes either surgery or radiotherapy; however, advanced cases often require surgery followed by radiation and chemotherapy. Salivary gland damage following radiotherapy leads to severe and chronic hypofunction with decreased salivary output, xerostomia, impaired ability to chew and swallow, increased risk of developing oral mucositis, and malnutrition. There is currently no standard of care for radiation-induced salivary gland dysfunction, and treatment is often limited to palliative treatment that provides only temporary relief. Adenosine monophosphate (AMP)-activated protein kinase (AMPK) is an enzyme that activates catabolic processes and has been shown to influence the cell cycle, proliferation, and autophagy. In the present study, we found that radiation (IR) treatment decreases tissue levels of phosphorylated AMPK following radiation and decreases intracellular NAD+ and AMP while increasing intracellular adenosine triphosphate. Furthermore, expression of sirtuin 1 (SIRT1) and nicotinamide phosphoribosyl transferase (NAMPT) was lower 5 d following IR. Treatment with AMPK activators, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) and metformin, attenuated compensatory proliferation (days 6, 7, and 30) following IR and reversed chronic (day 30) salivary gland dysfunction post-IR. In addition, treatment with metformin or AICAR increased markers of apical/basolateral polarity (phosphorylated aPKCζT560-positive area) and differentiation (amylase-positive area) within irradiated parotid glands to levels similar to untreated controls. Taken together, these data suggest that AMPK may be a novel therapeutic target for treatment of radiation-induced salivary damage.

This study aimed to investigate the recovery effect of Zuogui Jiangtang Qinggan Prescription on intestinal flora homeostasis control and intestinal mucosal barrier in type 2 diabetes mellitus(T2DM) with nonalcoholic fatty liver disease(NAFLD) induced by a high-fat diet. NAFLD was established in MKR transgenic mice(T2DM mice) by a high-fat diet(HFD), and subsequently treated for 8 weeks with Zuogui Jiangtang Qinggan Prescription(7.5, 15 g·kg~(-1)) and metformin(0.067 g·kg~(-1)). Triglyceride and liver function were assessed using serum. The hematoxylin-eosin(HE) staining and Masson staining were used to stain the liver tissue, while HE staining and AB-PAS staining were used to stain the intestine tissue. 16S rRNA sequencing was utilized to track the changes in the intestinal flora of the mice in each group. Polymerase chain reaction(PCR) and immunofluorescence were used to determine the protein and mRNA expression levels of ZO-1, Occludin, and Claudin-1. The results demonstrated that Zuogui Jiangtang Qinggan Prescription increased the body mass of T2DM mice with NAFLD and decreased the hepatic index. It down-regulated the serum biomarkers of liver function and dyslipidemia such as alanine aminotransferase(ALT), aspartate transaminase(AST), and triglycerides(TG), increased insulin sensitivity, and improved glucose tolerance. According to the results of 16S rRNA sequencing, the Zuogui Jiangtang Qinggan Prescription altered the composition and abundance of the intestinal flora, increasing the relative abundances of Muribaculaceae, Lactobacillaceae, Lactobacillus, Akkermansia, and Bacteroidota and decreasing the relative abundances of Lachnospiraceae, Firmicutes, Deslfobacteria, Proteobacteria, and Desulfovibrionaceae. According to the pathological examination of the intestinal mucosa, Zuogui Jiangtang Qinggan Prescritpion increased the expression levels of the tight junction proteins ZO-1, Occludin, and Claudin-1, promoted intestinal mucosa repair, protected intestinal villi, and increased the height of intestinal mucosa villi and the number of goblet cells. By enhancing intestinal mucosal barrier repair and controlling intestinal microbiota homeostasis, Zuogui Jiangtang Qinggan Prescription reduces intestinal mucosal damage induced by T2DM and NAFLD.

Metformin is an antidiabetic medicine widely used for management of type 2 diabetes with neuroprotective effects and promising potential to attenuate cognitive impairment. The efficacy of metformin in attenuation of Alzheimer's disease (AD) pathology has not been well-documented. Thus, this study was designed to assess protective effect of metformin against Aβ1-40-instigared cognitive impairment. After intra-CA1 microinjection of aggregated Aβ1-40, rats received oral metformin (50 and/or 200 mg/kg/day) for two weeks. Cognition function was analyzed in various behavioral tasks besides measurement of hippocampal oxidative stress, apoptosis, and inflammation along with H&E staining and 3-nitrotyrosine (3-NT) immunohistochemistry. Obtained data showed significant improvement of discrimination score in novel object recognition test, higher alternation score in Y maze, greater latency in passive avoidance task, and lower working and reference memory errors in radial arm maze in metformin-treated Aβ-injured group. Moreover, metformin treatment attenuated hippocampal levels of nitrite, MDA, protein carbonyl, ROS, TNFα, GFAP, DNA fragmentation intensity, caspase 3 activity, AChE activity, and increased SOD activity and level of IL-10 as an anti-inflammatory factor. In addition, metformin treatment was associated with lower CA1 neuronal loss and it also decreased intensity of 3-NT immunoreactivity as an indicator of nitrosative stress. Taken together, obtained findings showed neuroprotective and anti-dementia property of metformin in male rats and this may have potential benefit in attenuation of cognitive decline and related complications in patients with neurodegenerative disorders such as AD besides diabetes mellitus.